ROS-Responsive Polymeric Micelles for Triggered Simultaneous Delivery of PLK1 Inhibitor/miR-34a and Effective Synergistic Therapy in Pancreatic Cancer.
ROS-Responsive Polymeric Micelles for Triggered Simultaneous Delivery of PLK1 Inhibitor/miR-34a and Effective Synergistic Therapy in Pancreatic Cancer.
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DOI：
10.1021/acsami.9b02756
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发表时间：
2019-04
影响因子：
9.5
通讯作者：
X. Xin;Feng Lin;Qiyue Wang;Lifang Yin;R. Mahato
中科院分区：
文献类型：
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作者：
X. Xin;Feng Lin;Qiyue Wang;Lifang Yin;R. Mahato
无效的药物递送和预后不良是治疗胰管导管腺癌（PDAC）的两个主要挑战（PDAC），而肿瘤抑制MicroRNA-34A（miR-34a）的下调很大因此，目的用于使用聚（乙烯乙二醇） - 聚[aspartamidoethyl（p-硼苯基）二乙基氨基铵的二乙基氨基铵（Peg-b-paebea）（PEG-B-Paebea）的codeLiver miR-34a模拟和小分子PLK1抑制剂Volasertib（BI6727）（bi6727）。 miR-34a在18岁及以上的N/P比率较高。协同作用和抗增殖活性以及G2/m相的抑制和菌落形成的抑制，导致由于胶束摄入胶束和米尔氏症的米尔斯（Mir-cymers）的旋转，导致了原位的胰腺NSG小鼠，从而导致临床的细胞死亡血浆和主要器官的浓度由测量荧光强度，肿瘤的体积显着减少，并且主要的器官的组织学检查表明，携带volasertib和miR-34a模拟的PEG-B-PAEBEA胶束可忽略不计。
Ineffective drug delivery and poor prognosis are two major challenges in the treatment of pancreatic ductal adenocarcinoma (PDAC). While there is significant downregulation of tumor suppressor microRNA-34a (miR-34a), which targets many oncogenes related to proliferation, apoptosis, and invasion, high expression level of Polo-like kinase 1 (PLK1) is closely associated with short survival rates of pancreatic cancer patients. Therefore, the objective is to codeliver miR-34a mimic and small molecule PLK1 inhibitor volasertib (BI6727) using poly(ethylene glycol)-poly[aspartamidoethyl( p-boronobenzyl)diethylammonium bromide] (PEG-B-PAEBEA). This polymer could self-assemble into micelles of ∼100 nm with 10% drug loading of volasertib and form a complex with miR-34a at the N/P ratio of 18 and higher. Combination treatment of volasertib and miR-34a displayed the synergistic effect and superior antiproliferative activity along with an enhanced G2/M phase arrest and suppression of colony formation, leading to cell death due to potential c-myc targeting therapeutics. Orthotopic pancreatic tumor bearing NSG mice were scanned for fluorescence by IVIS after systemic administration of micelles encapsulating volasertib and miR-34a at doses of 5 and 1 mg/kg, respectively. Cy5.5 concentration in plasma and major organs was determined by measuring fluorescence intensity. There was significant reduction in tumor volume, and histological examination of major organs suggested negligible systemic toxicity. In conclusion, PEG-B-PAEBEA micelles carrying volasertib and miR-34a mimic have the potential to treat pancreatic cancer.